Throughout this application, various publications are referred to. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
Vitamin D and its derivatives have important physiological functions. For example, 1xcex1,25-dihydroxy vitamin D3 exhibits a broad range of physiological functions such as calcium metabolism-controlling activity, growth-inhibiting activity, differentiation-inducing activity on cells such as tumor cells, and immune-controlling activity. However, vitamin D3 derivatives exhibit undesirable side effects such as hypercalcemia.
Novel vitamin D derivatives have been developed to retain effectiveness in the treatment of specific diseases while reducing associated side effects.
For example, Japanese Patent No. 61-267550 (issued Nov. 27, 1986) discloses a 9,10-seco-5,7,10(19)-pregnatriene derivative which exhibits an immune-controlling activity and a differentiation-inducing activity on tumor cells. In addition, Japanese Patent No. 61-267550 (issued Nov. 27, 1986) also discloses two processes for preparing the final product, one using pregnenorone and the other dehydroepiandorosterone as the starting material.
1xcex1,25-dihydroxy-22-oxavitamin D3 (OCT), the 22-oxa analogue of 1xcex1,25-dihydroxyvitamin D3 has potent in vitro differentiation-inducing activities with low in vivo calcemic liability. OCT is being clinically investigated as a candidate for treatment of secondary hyperparathyroidism and psoriasis.
Japanese Patent No. 6-072994 (issued Mar. 15, 1994) discloses a 22-oxacholecalciferol derivative and a process for the preparation thereof. It discloses a process for preparing an oxacholecalciferol derivative which comprises reacting a pregnene derivative having a hydroxyl group at the 20-position with a dialkylacrylamide compound to give an ether compound and then reacting the thus-obtained ether compound with an organometal compound to give the desired compound.
Japanese Patent No. 6-080626 (issued Mar. 22, 1994) discloses a 22-oxavitamin D derivative. It also discloses a process which comprises reacting 1xcex1,3xcex2-bis(tert-butyldimethylsilyloxy)-pregne-5,7-diene-20(S or R)-ol as a starting compound with an epoxide in the presence of a base to give a compound having an ether bond at the 20-position.
In addition, Japanese Patent No. 6-256300 (issued Sep. 13, 1994) and Kubodera et al. (Bioorganic and Medicinal Chemistry Letters, 4(5): 753-756, 1994) disclose a process for stereospecifically preparing an epoxy compound which comprises reacting 1xcex1,3xcex2-bis(tert-butyldimethylsilyloxy)-pregna-5,7-diene-20(S)-ol with 4-(tetrahydropyran-2-yloxy)-3-methyl-2-butene-1-bromide to give an ether compound, deprotecting it, and subjecting the deprotected ether compound to Sharpless oxidation. However, the above processes require more than one step for introducing an ether bond and an epoxy group into a side chain of a steroid group and therefore, result in low yield of the desired compound.
Furthermore, none of the above references disclose a synthesis method in which an alcohol compound is reacted with an epoxy hydrocarbon compound having an eliminating group at its end, thereby forming an ether bond. Also, the above references do not disclose a bicyclo[4.3.0]nonane structure (hereinafter referred to as a CD ring structure), a steroid structure, or a vitamin D structure, each having an ether bond and an epoxy group at a side chain.
The present invention provides a process for preparing a compound having the structure of the following formula I: 
wherein n is an integer from 1-5; each of R1 and R2 independently is optionally substituted C1-C6 alkyl; each of W and X is independently hydrogen or C1-C6 alkyl; Y is O, S or NR3 where R3 is hydrogen, C1-C6 alkyl or a protective group; and Z is: 
where each of R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16, and R17 independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and each of R6 and R7 independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond; which comprises:
(a) reacting a compound having the following formula IV: 
xe2x80x83wherein W, X, Y and Z are as defined above, in the presence of a base, with a compound having the structure, of the following formula V or Vxe2x80x2: 
xe2x80x83wherein n, R1 and R2 are as defined above, and E is an eliminating group, to produce the compound of formula I; and
(b) recovering the compound so produced.
The present invention also provides a compound having the structure of the formula I: 
wherein n is an integer from 1-5; each of R1 and R2 independently is optionally substituted C1-C6 alkyl; each of W and X is independently hydrogen or C1-C6 alkyl; Y is O, S or NR3 where R3 is hydrogen, C1-C6 alkyl or a protective group; and Z is: 
where each of R4, R5; R8, R9, R10, R11, R12, R13, R14, R15, R16, and R17 independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and each of R6 and R7 independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond.
The present invention further provides a process for preparing a compound having the structure of the following formula VI: 
wherein n is an integer from 1-5; each of R1 and R2 independently is optionally substituted C1-C6 alkyl; each of W and X is independently hydrogen or C1-C6 alkyl; Y is O, S or NR3 where R3 is hydrogen, C1-C6 alkyl or a protective group; and Z is: 
where each of R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16, and R17 independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and each of R6 and R7 independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond; which comprises:
(a) reacting a compound having the following formula IV: 
xe2x80x83wherein W, X, Y and Z are as defined above, in the presence of a base, with a compound having the structure of the following formula V or formula Vxe2x80x2: 
xe2x80x83wherein n, R1 and R2 are as defined above, and E is an eliminating group, to produce an epoxide compound having the structure of formula I: 
(b) treating the epoxide compound with a reducing agent to produce the compound of formula VI; and
(c) recovering the compound so produced.
The present invention further provides a process for preparing a compound having the structure: 
wherein n is an integer from 1-5; each of R1 and R2 independently is optionally substituted C1-C6 alkyl; each of W and X is independently hydrogen or C1-C6 alkyl; Y is O, S or NR3 where R3 is hydrogen, C1-C6 alkyl or a protective group; and Zxe2x80x2 is a vitamin D structure optionally having one or more protected or unprotected substituents and/or one or more protective groups, wherein Zxe2x80x2 is preferably: 
where each of R10, R11, R12, and R13 independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl;
which comprises:
(a) reacting a compound having the structure: 
xe2x80x83wherein W, X, and Y are as defined above and Zxe2x80x3 represents a steroid structure optionally having one or more protected or unprotected substituents and/or one or more protective groups, Zxe2x80x3 most preferably being: 
xe2x80x83where each of R4, R5, R8, and R9 independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and each of R6 and R7 independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond, in the presence of a base, with a compound having the structure: 
xe2x80x83wherein n, R1 and R2 are as defined above, and E is an eliminating group, to produce an epoxide compound having the structure: 
(b) treating the thus obtained epoxide compound with a reducing agent to produce the reduced compound VI;
(c) subjecting the thus obtained reduced steroid compound to ultraviolet irradiation and heat isomerization under conditions permitting the steroid structure of Zxe2x80x3 to be converted to the vitamin D structure of Zxe2x80x2; and
(d) recovering the compound so produced.
The present invention further provides a process for preparing a compound having the structure: 
wherein n is an integer from 1-5; each of R1 and R2 independently is optionally substituted C1-C6 alkyl; each of W and X is independently hydrogen or C1-C6 alkyl; Y is O, S or NR3 where R3 is hydrogen, C1-C6 alkyl or a protective group; and Zxe2x80x2 is a vitamin D structure optionally having one or more protected or unprotected substituents and/or one or more protective groups, wherein Zxe2x80x2 is preferably: 
where each of R10, R11, R12, and R13 independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl;
which comprises:
(a) reacting a compound having the structure: 
xe2x80x83wherein W, X, and Y are as defined above and Zxe2x80x2xe2x80x3 represents a CD ring structure optionally having one or more protected or unprotected substituents and/or one or more protective groups, Zxe2x80x2xe2x80x3 most preferably being: 
xe2x80x83where each of R14, R15, R16, and R17 independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl, in the presence of a base, with a compound having the structure: 
xe2x80x83wherein n, R1 and R2 are as defined above, and E is an eliminating group, to produce an epoxide compound having the structure: 
(b) treating the thus obtained epoxide compound with a reducing agent to produce the reduced compound;
(c) reacting the thus obtained reduced CD ring compound with a building block capable of producing the ring structure of vitamin D under conditions permitting the CD structure of Zxe2x80x2xe2x80x3 to be converted to the vitamin D structure of Zxe2x80x2; and
(d) recovering the compound so produced.
The present invention provides a process for preparing a compound having the structure: 
wherein n is an integer from 1-5; each of R1 and R2 independently is optionally substituted C1-C6 alkyl; each of W and X is independently hydrogen or C1-C6 alkyl; Y is O, S or NR3 where R3 is hydrogen, C1-C6 alkyl or a protective group; and Z is: 
where each of R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16, and R17 independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and each of R6 and R7 independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond; which comprises:
(a) reacting a compound having the structure: 
xe2x80x83wherein W, X, Y and Z are as defined above, in the presence of a base, with a compound having the structure: 
xe2x80x83wherein n, R1 and R2 are as defined above, and E is an eliminating group, to produce the compound; and
(b) recovering the compound so produced.
The term xe2x80x9celiminating groupxe2x80x9d as used herein means a group capable of reacting with xe2x80x94YH group as defined above to eliminate HE and form xe2x80x94Yxe2x80x94 bond. Exemplary eliminating groups include a halogen atom such as fluorine, chlorine, bromine or iodine, a tosyl group, a mesyl group, a trifluoromethanesulfonyl group, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and an imidate group, with a halogen atom being preferred, with a bromine atom being particularly preferred.
The process for preparing a compound having the structure: 
is novel and is useful for the synthesis of vitamin D derivatives which can have a variety of physiological activities such as differentiation-inducing activity and a growth-inhibiting activity on cells.
The present invention also provides that in the compounds having the structure: 
Z represents a CD ring structure, a steroid structure or a vitamin D structure, each of which optionally has one or more protected or unprotected substituents and/or more protective groups. Each of the CD ring structure, steroid structure and vitamin D structure for the present invention particularly means a structure as described below, any ring of which may optionally have one or more unsaturated bonds. In the steroid structure, one having one or two unsaturated bonds are preferred, and 5-ene steroid compound, 5,7-diene steroid compound, or a protected compound thereof, are particularly preferred. 
The substituents on Z which is the CD structure, steroid structure, or vitamin D structure are not particularly limited but may be exemplified by a hydroxyl group, a substituted or unsubstituted lower alkyloxy group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylidene group, a carbonyl group and an oxo group (xe2x95x90O), with a hydroxyl group being preferred. These substituents may be protected. Useful protective groups are not particularly limited but include an acyl group, a substituted silyl group and a substituted or unsubstituted alkyl group, with an acyl group and a substituted silyl group being preferred. Examples of the acyl group include an acetyl group, a benzoyl group, a substituted acetyl group and a substituted benzoyl group, as well as carbonate types and carbamate types, with an acetyl group being preferred. Examples of substituents on the said acetyl and benzoyl groups include a halogen atom, an alkyl group, an alkenyl group and an aryl group, with a fluorine atom, a chlorine atom, a methyl group, a phenyl group and an ethylidene group being preferred. Preferred examples of the substituted acetyl group include a chloroacetyl group, a trifluoracetyl group, a pivaloyl group and a crotonoyl group. Preferred examples of the substituted benzoyl group include a p-phenylbenzoyl group and a 2,4,6-trimethylbenzoyl group. Examples of the substituted silyl group include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl (TBS) group and a tert-butyldiphenylsilyl group, with a tert-butyldimethylsilyl (TBS) group being preferred. Examples of the substituted or unsubstituted alkyl group include a methyl group, a methoxymethyl group, a methylthiomethyl group, tert-butylthiomethyl group, a benzyloxymethyl group, a p-methoxybenzyloxymethyl group, a 2-methoxyethoxymethyl group, a tetrahydropyranyl group, a tert-butyl group, an allyl group, a benzyl group, a p-methoxybenzyl group, and an o- or p-nitrobenzyl group.
Examples of a protective group for an unsaturated bond in the steroid structure include 4-phenyl-1,2,4-triazoline-3,5-dione and diethyl maleate. An example of adducts having such protective group is the following: 
Furthermore, the vitamin D structure may be protected by addition of SO2. Examples of such protected vitamin D structures are given below: 
In the formulae I, V, Vxe2x80x2 and VI according to the present invention, R1 and R2, which may be the same or different, each represents a substituted or unsubstituted lower alkyl group, with an unsubstituted lower alkyl group being preferred. In the definition of R1 and R2, the lower alkyl group means a straight or branched alkyl group having 1-6 carbon atoms. Examples of the lower alkyl group include a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, a s-butyl group, and a t-butyl group, with a methyl group and an ethyl group being particularly preferred. In the definition of R1 and R2, the substituents on the substituted alkyl group may be exemplified by a hydroxyl group and an amino group, with a hydroxyl group being preferred.
In the formulae I, IV and VI according to the present invention, W and X, which may be the same or different, each represents a hydrogen atom or a straight or branched lower alkyl group. Preferably, one of W and X is an alkyl group, most preferably a methyl group, and the other is a hydrogen atom. Particularly preferably, W is a methyl group and X is a hydrogen atom.
In the formulae I, IV and VI according to the present invention, Y represents O, S or NR3 wherein R3 represents a hydrogen atom or a protective group. Examples of the protective group in R3 include a substituted or unsubstituted carbamate group, a substituted or unsubstituted amide group and a substituted or unsubstituted alkyl group, alkyl preferably being C1-C6 alkyl, with a methyl carbamate group, an ethyl carbamate group, a trichloroethylcarbamate group, a t-butylcarbamate group, a benzylcarbamate group, an acetoamide group, a trifluoroacetoamide group, a methyl group and a benzyl group being preferred. Y is preferably O or S, with O being particularly preferred.
In the formulae I, V, Vxe2x80x2 and VI according to the present invention, n is 1, 2, 3 or 4, preferably 1 or 2, particularly preferably 1. Preferably, when n is 1 and where one of R1 and R2 is a methyl group, the other is not a hydroxymethyl group.
A particularly preferred embodiment of the compound represented by the formula I according to the present invention is such that the formula I, R1 and R2 are the same and each represents a methyl group or an ethyl group, W and X are different and each represents a hydrogen atom or a methyl group, Y represents O, and n represents 1 or 2.
The more preferred examples of the compound represented by the formula I according to the present invention are represented by the following formulae IIA and IIB: 
wherein R18 and R19, which may be the same or different, each represents a hydrogen atom or a protective group; or the following formulae IIIA and IIIB: 
wherein R18 and R19, which may be the same or different, each represents a hydrogen atom or a protective group.
The most preferred example of the compound represented by the formula I according to the present invention is represented by the above formulae IIA and IIB.
An outline of the reaction disclosed herein for the production of the compound of formula I is shown in the following reaction scheme A. 
Some of the compounds which are used as a starting compound in the above-mentioned process according to the present invention, are known compounds. For example, when xe2x80x9cYxe2x80x9d is O, the following can be used as the starting compounds: the 1xcex1,3xcex2-bis(tert-butyldimethylsilyloxy)-pregna-5,7-diene-20(S)-ol described in Japanese Patent No. 61-267550 (issued Nov. 27, 1986); the 9,10-seco-5,7,10(19)-pregnatriene-1xcex1,3xcex2,20xcex2-triol optionally with the hydroxyl group being protected described in Japanese Patent No. 61-267550 (issued Nov. 27, 1986) and International Patent Publications WO 90/09991 (Sep. 7, 1990) and WO 90/09992 (Sep. 7, 1990); the octahydro-4-(t-butyldimethylsilyloxy)-7-methyl-1H-indene-1-ol described in J. Org. Chem., 57, 3173 (1992); and the octahydro-4-(acetyloxy)-7-methyl-1H-indene-1-ol described in J. Am. Chem. Soc., 104, 2945 (1982).
When xe2x80x9cYxe2x80x9d is S, a starting compound (formula IV) having a thiol group (xe2x80x94SH-group) at 20-position may be used instead of the said compound having a hydroxyl group at 20-position. Such a compound can be obtained, for example, by converting a ketone compound to a thiol compound in accordance with a previously described method (Journal of the American Chemical Society, 102:10 [1980] pp. 3577-3583). More particularly, the ketone compound is reacted with 1 equivalent of 1,2-ethanedithiol in the presence of a catalyst to prepare the corresponding ethylene thioketal compound, and then the thus-obtained ethylene thioketal compound is reacted with 3-4 equivalents of n-butyllithium to yield the corresponding thiol compound. Alternatively, such a thiol compound can be synthesized from a compound having an aldehyde group or a protected hydroxyl group at 20-position in accordance with the method described in International Patent Publication WO 94/14766 (Jul. 7, 1994).
Furthermore, starting compounds wherein xe2x80x9cYxe2x80x9d is NR3 (where R3 represents a hydrogen atom or a protective group), are also known and disclosed (Chem. Pharm. Bull. Vol. 32, pp. 1416-1422 [1984]).
Some of the compounds having the structure: 
which are used as a reactant in the above-mentioned process according to the present invention, are known compounds and can be prepared in accordance with a known method by reacting an alkenyl compound having an eliminating group at its end with an organic peracid such as m-chloroperbenzoic acid (mCPBA) in an inert organic solvent. xe2x80x9cEExe2x80x9d represents an eliminating group. The term xe2x80x9celiminating groupxe2x80x9d as used herein means a group capable of reacting with xe2x80x94YH group in formula IV to eliminate HE and form xe2x80x94Yxe2x80x94 bond. Exemplary eliminating groups include a halogen atom such as fluorine, chlorine, bromine or iodine, a tosyl group, a mesyl group, a trifluoromethanesulfonyl group, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and an imidate group, with a halogen atom being preferred, with a bromine atom being particularly preferred.
The above-mentioned reaction (scheme A) according to the present invention is carried out in the presence of a base. Examples of the base that can be used include alkali metal hydrides, alkali metal hydroxides and alkali metal alkoxides, with alkali metal hydrides being preferred, with sodium hydride being particularly preferred.
The reaction is preferably carried out in an inert solvent. Examples of the solvent that can be used include ether solvents, saturated aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, amide solvents, and combinations thereof, with dimethylformamide (DMF), tetrahydrofuran (THF), benzene, toluene, diethyl ether, and a mixture of DMF and diethyl ether, being preferred, with dimethylformamide and tetrahydrofuran being more preferred.
The reaction temperature may appropriately be controlled, generally in the range from 25xc2x0 C. to a reflux temperature of a solvent, preferably from 40xc2x0 C. to 65xc2x0 C.
The reaction time may appropriately be controlled, generally in the range from 1 hour to 30 hours, preferably from 2 hours to 5 hours. The progress of the reaction my be monitored by thin layer chromatography (TLC).
In one embodiment of the present invention, the process for preparing a compound having the structure: 
comprises:
(a) reacting a compound having the structure: 
xe2x80x83in the presence of a base, with a compound having the structure: 
xe2x80x83to produce the compound; and
b) recovering the compound so produced.
In another embodiment of the present invention, the process for preparing a compound having the structure: 
comprises:
(a) reacting a compound having the structure: 
xe2x80x83in the presence of a base, with a compound having the structure: 
xe2x80x83to produce the compound; and
b) recovering the compound so produced.
In yet another embodiment of the present invention, the process for preparing a compound having the structure: 
comprises:
(a) reacting a compound having the structure: 
xe2x80x83in the presence of a base, with a compound having the structure: 
xe2x80x83to produce the compound; and
b) recovering the compound so produced.
In another embodiment of the present invention, the process for preparing a compound having the structure: 
comprises:
(a) reacting a compound having the structure: 
xe2x80x83in the presence of a base, with a compound having the structure: 
xe2x80x83to produce the compound; and
b) recovering the compound so produced.
In yet another embodiment of the present invention, recovery of the compound comprises filtration or chromatography.
In another embodiment of the present invention, the eliminating group is halogen, mesyl, tosyl, imidate, trifluoromethanesulfonyl, or phenylsulfonyl.
In yet another embodiment of the present invention, the halogen is bromine.
In another embodiment of the present invention, the base is alkali metal hydride, alkali metal hydroxide, or alkali metal alkoxide.
In yet another embodiment of the present invention, the alkali metal hydride is NaH or KH.
In another embodiment of the present invention, the base is NaOR20, KOR20, R20Li, NaN(R21)2, KN(R21)2, or LiN(R21)2; R20 is alkyl; and R21 is isopropyl or (CH3)3Si.
The present invention also provides a compound having the structure: 
wherein n is an integer from 1-5; each of R1 and R2 independently is optionally substituted C1-C6 alkyl; each of W and X is independently hydrogen or C1-C6 alkyl; Y is O, S or NR3 where R3 is hydrogen, C1-C6 alkyl or a protective group; and Z is: 
where each of R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16, and R17 independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and each of R6 and R7 independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond.
The compound having the structure: 
is a novel compound and a useful intermediate for the synthesis of vitamin D derivatives which can have a variety of physiological activities such as differentiation-inducing activity and a growth-inhibiting activity on cells.
In one embodiment of the present invention, the compound has the structure: 
In another embodiment of the present invention, the compound has the structure: 
In yet another embodiment of the present invention, the compound has the structure: 
In another embodiment of the present invention, the compound has the structure: 
The present invention further provides a process for preparing a compound having the structure: 
wherein n is an integer from 1-5; each of R1 and R2 independently is optionally substituted C1-C6 alkyl; each of W and X is independently hydrogen or C1-C6 alkyl; Y is O, S or NR3 where R3 is hydrogen, C1-C6 alkyl or a protective group; and Z is: 
where each of R4, R5, R8, R9, R10, R11, R12, R13, R14, R15, R16, and R17 independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and each of R6 and R7 independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond; which comprises:
(a) reacting a compound having the structure: 
xe2x80x83wherein W, X, Y and Z are as defined above, in the presence of a base, with a compound having the structure: 
xe2x80x83wherein n, R1 and R2 are as defined above, and E is an eliminating group, to produce an epoxide compound having the structure: 
(b) treating the epoxide compound with a reducing agent to produce the compound; and
(c) recovering the compound so produced.
The present invention relates to a process for preparing vitamin D or steroid derivatives via the novel intermediates described hereinabove. An outline of this reaction is shown in the following reaction scheme B. 
The reaction in step (1) of the above-mentioned two-step reaction according to the present invention can be carried out in the same way as in the process of Reaction Scheme A, which was already described herein.
The reaction in the step (2) is a reaction to open the epoxy ring in the epoxy compound obtained in step (1) and it is carried out using a reducing agent. The reducing agent which can be used in step (2) is such that it is capable of opening the ring of an epoxy compound obtained in step (1) to give a hydroxyl group, preferably capable of selective formation of a tertiary alcohol.
Examples of the reducing agent are listed below:
Lithium aluminumhydride [LiAlH4];
Lithium triethylborohydride [LiEt3BH, Super-Hydride];
Lithium tri-sec-butylborohydride [Li(s-Bu)3BH, L-Selectride];
Potassium tri-sec-butylborohydride [K(s-Bu)3BH, K-Selectride];
Lithium trisiamylborohydride [LiB[CH(CH3)CH(CH3)2]3H, LS-Selectride];
Potassium trisiamylborohydride [KB[CH(CH3)CH(CH3)2]3H, KB(Sia)3H, KS-Selectride];
Lithium dimethylborohydride [LiB(CH3)2H2];
Lithium thexylborohydride [Li[(CH3)2CHC(CH3)2BH3];
Lithium thexyllimonylborohydride; 
Lithium tri-tert-butoxyaluminohydride [LiAl[OC(CH3)3]3H];
Potassium tris(3,5-dimethyl-1-pyrazolyl)borohydride; 
KB(C6H5)3H;
Lithium 9-BBN hydride; 
NaBH4;
NaBH3CN.
Moreover, an additive such as lithium salts, preferably lithium halides such as lithium bromide (LiBr) and lithium iodide (LiI), particularly preferably LiI, may be added to the reducing agent, particularly in the case where the reducing agent contains potassium.
Preferred examples of the reducing agent are listed below:
Lithium aluminumhydride [LiAlH4];
Potassium tri-sec-butylborohydride [K(s-Bu)3BH, L-Selectride]+LiI;
Lithium triethylborohydride [LiEt3BH, Super-Hydride];
Lithium tri-sec-butylborohydride [Li(s-Bu)3BH, L-Selectride];
Lithium 9-BBN hydride.
Particularly preferred examples of the reducing agents are listed below:
Lithium triethylborohydride [LiEt3BH, Super-Hydride];
Lithium tri-sec-butylborohydride [Li(s-Bu)3BH, L-Selectride];
Lithium 9-BBN hydride.
It is also possible to preferentially obtain a compound having a hydroxyl group at 24-position of the vitamin D compound by selecting a suitable reducing agent, such as, for example, diisobutylaluminumhydride (DIBAL-H).
The reaction in step (2) is preferably carried out in an inert solvent. Examples of the solvent that can be used include diethylether, tetrahydrofuran (THF), dimethylformamide (DMF), benzene and toluene, with diethylether and tetrahydrofuran being preferred.
The reaction temperature in step (2) may appropriately be controlled, generally in the range from 10xc2x0 C. to 100xc2x0 C., preferably from room temperature to 65xc2x0.
The reaction time in step (2) may appropriately be controlled, generally in the range from 30 minutes to 10 hours, preferably from 1 hour to 5 hours. The progress of the reaction can be monitored by thin layer chromatography (TLC).
The reaction in step (2) can be carried out after step (1), more specifically after the purification of the reaction product of step (1) by means of a suitable method such as silica gel chromatography, or alternatively, it can be carried out by directly adding a reducing agent to a mixture containing the reaction product of step (1) without purifying it. The process where step (2) is carried out after step (1) without purification of the product is referred to as xe2x80x9cone-pot reactionxe2x80x9d and this is preferred since it is operationally less tedious.
A greatly preferred and surprisingly superior one-pot reaction has been discovered which permits excellent yield of compound VI directly from compound I, without first purifying the intermediate compound IV, while using a relatively small amount of the reactant of formula V, as well as a relatively small amount of base. This improved process is obtained by using THF as the solvent. Neither DMF nor a combination of DMF and dimethyl ether will permit one-pot conversion. The choice of reducing agent is also important to achieve the best one-pot yields. For the preferred one-pot process, the preferred reducing agent is L-Selectride, K-Selectride with LiI as an additive, lithium 9-BBN hydride or Super-Hydride. LiAlH4 can also be used as the reducing agent in the improved one-pot process, although one will not achieve as high a conversion to the desired product using the latter reducing agent. Using the preferred solvent (THF) and reducing agent, one can reduce the mole equivalent of base which is used in the reaction to as low as 1.5 and the mole equivalent of the reagent of formula V to the substrate to only 1.3, while still obtaining almost 100% conversion to the desired stereospecific product.
The following Reaction Scheme C shows reaction routes using the compounds and processes of the present invention. Processes for the synthesis of a vitamin D compound from the corresponding steroid compound can be carried out by a conventional process such as ultraviolet irradiation and heat isomerization. Processes for the synthesis of a vitamin D compound from the corresponding CD ring compound are also conventional. Such processes are described in, for example, E. G. Baggiolini et al., J. Am. Chem. Soc., 104, 2945-2948 (1982) and Wovkulich et al., Tetrahedron, 40, 2283 (1984). It should be understood that a part or all of the processes shown in Reaction Scheme C are embraced within the present invention.
Reaction Scheme C 
(Wherein W, X, Y, O, R1, and R2 are the same as defined hereinabove, and any ring of the structure may optionally have one or two unsaturated bonds).
Particularly preferred examples of the vitamin D derivatives of the final product, which can be obtained by utilizing the present invention, are represented by the following formulae VII and VIII: 
the most preferred example being represented by the formula VII.
In one preferred embodiment of the present invention, the process for preparing a compound having the structure: 
comprises:
a) reacting a compound having the structure: 
xe2x80x83in the presence of a base, with a compound having the structure: 
xe2x80x83to produce an epoxide compound having the structure: 
(b) treating the epoxide compound with a reducing agent to produce the compound; and
(c) recovering the compound so produced.
In another embodiment of the present invention, the process for preparing a compound having the structure: 
comprises:
a) reacting a compound having the structure: 
xe2x80x83in the presence of a base, with a compound having the structure: 
xe2x80x83to produce an epoxide compound having the structure: 
(b) treating the epoxide compound with a reducing agent to produce the compound; and
(c) recovering the compound so produced.
In yet another embodiment of the present invention, the process for preparing a compound having the structure: 
comprises:
a) reacting a compound having the structure: 
xe2x80x83in the presence of a base, with a compound having the structure: 
xe2x80x83to produce an epoxide compound having the structure: 
(b) treating the epoxide compound with a reducing agent to produce the compound; and
(c) recovering the compound so produced.
In another embodiment of the present invention, the process for preparing a compound having the structure: 
comprises reacting a compound having the structure: 
in the presence of a base, with a compound having the structure: 
to produce an epoxide compound having the structure: 
(b) treating the epoxide compound with a reducing agent to produce the compound; and
(c) recovering the compound so produced.
In yet another embodiment of the present invention, recovery of the compound comprises filtration or chromatography.
In yet another embodiment of the present invention, the eliminating group is halogen, mesyl, tosyl, imidate, trifluoromethanesulfonyl, or phenylsulfonyl.
In another embodiment of the present invention, the halogen is bromine.
In yet another embodiment of the present invention, the base is alkali metal hydride, alkali metal hydroxide, or alkali metal alkoxide.
In another embodiment of the present invention, the alkali metal hydride is NaH or KH.
In yet another embodiment of the present invention, the base is NaOR20, KOR20, R20Li, NaN(R21)2, KN(R21)2, or LiN(R21)2; R20 is alkyl; and R21 is isopropyl or (CH3)3Si.
In another embodiment of the invention, the reducing agent is LiAlH4, Li(s-Bu)3BH, or LiEt3BH.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.